Devices and methods for pain management

ABSTRACT

The invention features devices and methods for the systemic delivery of fentanyl or a fentanyl congener (e.g., sufentanil) to treat pain. In the present invention, a drug formulation comprising fentanyl or a fentanyl congener is stored within a drug delivery device (e.g., contained in a reservoir or impregnated within a matrix within the controlled drug delivery device). The drug formulation comprises an amount of drug sufficient for treatment and is stable at body temperatures (i.e., no unacceptable degradation) for the entire pre-selected treatment period. The drug delivery devices store the drug formulation safely (e.g., without dose dumping), provide sufficient protection from bodily processes to prevent unacceptable degradation of the formulation, and release the drug formulation in a controlled fashion at a therapeutically effective rate to treat pain. In use, the drug delivery device is implanted in the subject&#39;s body at an implantation site, and the drug formulation is released from the drug delivery device to a delivery site. The delivery site may be the same as, near, or distant from the implantation site. Once released at the delivery site, the drug formulation enters the systemic circulation and is transported to the site of action in the body to modulate the pain response (e.g., the brain or other pain sensory location).

This application is a continuation of co-pending U.S. application Ser.No. 10/719,007, filed on Nov. 20, 2003, incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates to devices and methods for the management of pain.

BACKGROUND OF THE INVENTION

Many medications are used for the treatment of pain, ranging from wellknown, over-the-counter compounds such as aspirin, acetominophen,ibuprofen and other non-steroidal anti-inflammatory compounds to thenewly developed chemical entities such as the cyclooxygenase IIinhibitor compounds. Opiates in various forms, including opium, heroineand morphine which derive from the opium poppy, have very powerfulanalgesic properties. Opiates have been widely used for anesthesia aswell for the treatment of pain, especially where the pain is verysevere. In addition to these natural opiates, many synthetic opioidshave since been synthesized including methadone, fentanyl and congenersof fentanyl such as sufentanil, alfentanil, lofentanil, carfentanil,remifentanil, etc. Of the opioids, morphine is still the drug of choicefor management of pain at least in part due to its low cost, the abilityof the drug to provide relief from pain of a variety of origins, and thevast experience with this drug. Despite its therapeutic advantages andvast experience with the drug, many pain management experts believe thatmorphine and other opioids are under-prescribed for patients who requirelong-term pain therapy.

One reason for underprescription is the risk of the side effectsassociated with long-term administration of opioids in general, such asdevelopment of opiate tolerance, dependence, constipation, and/or otherundesirable side effects (see, e.g., Moulin et al. 1992 Can Med. Assoc.J. 146:891-7). Patients who develop opioid tolerance require increaseddoses to achieve a satisfactory analgesic effect, and risk thedevelopment of further undesirable side effects such as respiratorydepression, which can be life threatening. Physical dependence, which isrelated to factors such as the dose administered and the length of theadministration period, can generally only be resolved by discontinuingopioid administration, which in turn results in the onset of severelypainful withdrawal symptoms. Other side effects that can be associatedwith administration of opioids include reduced cough reflex, bronchialspasms, nausea, vomiting, peripheral vasodilation, orthostatichypotension, vagal impact on the heart, contraction of smooth muscles(sphincters), reduced peristaltic motility in the gastrointestinal tract(e.g., constipation), urinary retention, changes in regulation of bodytemperature and sleep pattern, and release of histamine, adrenalin, andanti-diuretic hormone. The negative effects on respiratory functionespecially impact postoperative patients, who are particularlysusceptible to depression of respiratory function. Even where theconcerns regarding side effects might be outweighed by the serious needfor pain relief as in terminally ill patients, many doctors still avoidprescribing opioids due to concerns of abuse of surplus medication byothers in contact with the patient, or even that their frequentprescription of the drug might lead to criminal investigation.

In addition to the disadvantages listed above pertaining to opioids ingeneral, morphine itself has also been associated with particular sideeffects, at times so severe as to make such therapy intolerable,especially for patients who are on long-term pain therapy or who requirehigh doses of medication to obtain relief. Some of these side effectsassociated with morphine usage, particularly at high doses, includenausea and vomiting (see for example Paix et al. (1995) Pain 63:263-9)and severe constipation. In addition, Sjorgen et al. (1994 Pain59:313-316) have reported the phenomena of hyperalgesia (increasedresponse to certain stimulus which is not normally painful), allodynia(sensation of pain felt even when stimulus is not normally painful) andmyoclonus associated with morphine use. It has been hypothesized thatmorphine and its metabolites may induce such abnormal sensitivity (see,e.g., Sjorgen et al. (1994) Pain 59:313-316).

Fentanyl and its congeners were originally developed as anesthesiaagents, and are generally used in the United States for the limitedpurposes of intravenous administration in balanced general anesthesia,as a primary anesthetic, or, in the case of sufentanil, for epiduraladministration during labor and delivery. However, these drugs also havepowerful analgesic properties and are several hundred or thousand timesmore potent than morphine depending on the particular congener. A fewstudies have in fact suggested that fentanyl and its congeners be usedinstead of morphine due to their increased potency and decreased sideeffects relative to morphine (see e.g., Sjorgen et al. (1994) Pain59:313-316 and Paix et al. (1995) Pain 63:263-9). Fentanyl and itscongeners are, however, more difficult to administer than morphine sincethey are not orally absorbed, are extremely potent (requiring veryprecise, accurate dosing of small amounts) and have very short halflives in the body thus requiring frequent dosing. For these reasons,conventional methods for delivery of opioid analgesics are inadequate tomeet these delivery requirements. For example, fentanyl has beenadministered in single, small intravenous doses, but this method ofadministration, besides being impractical for long-term therapy, resultsin a short duration of action and rapid recovery due to a redistributioninto fat stores and a rapid decline in plasma concentration. Thedevelopment of transdermal patch delivery technology allowed fentanyl tobe delivered continuously through the skin (e.g., the commercialDuragesic™ transdermal patch). Since the transdermal delivery methodprovided for constant drug delivery, it was a marked improvementrelative to bolus injection; however, transdermal delivery also hasseveral limitations. For example, transdermal delivery isdisadvantageous in that the dose of drug that can be delivered islimited by the available skin surface area, thus making transdermaldelivery suitable for low-to-medium opioid dose requirements, but ofteninadequate for more high dose requirements. In addition, transdermaldelivery of drug is disadvantageous in that there is a delay inobtaining steady state plasma concentrations upon initiation of therapy,as well as a prolonged period of continued effect even after removal ofthe patch. Other problems associated with transdermal delivery includeskin irritation, loss of adhesion after exposure to moisture (e.g.,perspiration, bathing) the potential for diversion of drug for illicitpurposes and patient distaste for the unsightliness of highly visiblepatches.

While subcutaneous infusion of fentanyl and sufentanil have been thesubject of experimentation on a limited basis, the methods disclosed inthe prior art are impractical as long-term pain therapies. Paix et al.(1995 Pain 63:263-9), for example, discloses the use of subcutaneousfentanyl and sufentanil as an alternative therapy in a small number ofpatients who suffered significant side effects associated withadministration of morphine. In Paix et al., the drug was infused intothe subcutaneous space at relatively large volume rates (e.g., on theorder of 3 mL/day to 40 mL/day) via an external syringe driver. Thetreatment method disclosed by Paix et al. has several majordisadvantages that render it impractical for long-term therapy. First,the provision of drug from an external source adversely affects mobilityof the patient and is therefore inconvenient for ambulatory patients,increases the risk of infections at the subcutaneous delivery site andprovides an opportunity for drug to be diverted for illicit uses.Second, the infusion of large volumes of fluid may result in tissuedamage or edema at the site of infusion. In addition, the absorptivecapacity of the subcutaneous space limits the volume of fluid that canbe delivered (see, e.g., Anderson et al., supra), and this volumetriclimitation can in turn limit the amount of drug that can be administered(e.g., in Paix et al., more potent opioids were administered to somepatients requiring high doses since the volume of morphine required wastoo large to be effectively absorbed in the subcutaneous tissues).

As is evident from the above, there is a great need for devices andmethods for effective and practical management of pain, particularlypain of long duration, with better efficacy and reduced side effects.The present invention addresses this problem.

SUMMARY OF THE INVENTION

The invention features devices and methods for the systemic delivery offentanyl or a fentanyl congener (e.g., sufentanil) to treat pain. In thepresent invention, a drug formulation comprising fentanyl or a fentanylcongener is stored within a drug delivery device (e.g., contained in areservoir or impregnated within a matrix within the controlled drugdelivery device). The drug formulation comprises an amount of drugsufficient for treatment and is stable at body temperatures (i.e., nounacceptable degradation) for the entire pre-selected treatment period.The drug delivery devices store the drug formulation safely (e.g.,without dose dumping), provide sufficient protection from bodilyprocesses to prevent unacceptable degradation of the formulation, andrelease the drug formulation in a controlled fashion at atherapeutically effective rate to treat pain. In use, the drug deliverydevice is implanted in the subject's body at an implantation site, andthe drug formulation is released from the drug delivery device to adelivery site. The delivery site may be the same as, near, or distantfrom the implantation site. Once released at the delivery site, the drugformulation enters the systemic circulation and is transported to thesite of action in the body to modulate the pain response (e.g., thebrain or other pain sensory location).

In one aspect the invention features devices for and methods of treatingpain in a subject suffering from pain comprising systemic delivery of aformulation comprising fentanyl or fentanyl congener to the subject viaan implantable drug delivery device, where such formulation is deliveredat a rate sufficient to ameliorate pain. In specific embodiments, theformulation comprises sufentanil, which can be administered at a rate offrom about 0.01 μg per hour to 200 μg per hour.

In another aspect, the invention features devices for and methods oftreating pain by systemic delivery of a formulation comprising fentanylor fentanyl congener to the subject via an implantable drug deliverydevice for a pre-selected period at a low volume rate (e.g., from about0.01 μl/day to 2 ml/day).

In another aspect, the invention features devices for and methods oftreating pain in a subject comprising the steps of implanting a drugdelivery device at an implantation site in the body of a subject, wherethe drug delivery device is capable of controlled drug release; anddelivering a formulation comprising fentanyl or a fentanyl congener fromthe device to a delivery site for entering into the systematiccirculation in an amount effective to alleviate pain in the subject.

In various exemplary embodiments of the invention and various aspectsthereof, drug of the drug formulation administered is delivered at a lowdose rate due the potency of the subject drugs, e.g., from about 0.01μg/hr or 0.1 μg/hr, 0.25 μg/hr, 1 μg/hr, generally up to about 200μg/hr. Specific ranges of amount of drug delivered will vary dependingupon, for example, the potency and other properties of the drug used andthe therapeutic requirements of the subject. In one specific embodiment,the formulation comprises sufentanil and, in a specific embodiment, isdelivered at a rate of from about 0.01 μg/hr or 0.1 μg/hr, 0.25 μg/hr, 1μg/hr, generally up to about 200 μg/hr.

In another exemplary embodiment, the drug formulation is delivered at alow volume rate e.g., a volume rate of from about 0.01 μl/day to about 2ml/day.

In another exemplary embodiment, delivery of the formulation issubstantially continuous, and can be for a pre-selected administrationperiod ranging from several hours to years, preferably from about 4weeks to 12 months.

The drug delivery device can be any implantable device, which device canbe based on, for example, diffusive, erodible or convective systems,e.g., osmotic pumps, biodegradable implants, electrodiffusion systems,electroosmosis systems, vapor pressure pumps, electrolytic pumps,effervescent pumps, piezoelectric pumps, erosion-based systems, orelectromechanical systems.

Pain amenable to alleviation includes, but is not necessarily limited tovarious types of acute or chronic pain, including cancer pain,inflammatory disease pain, neuropathic pain, nociceptive pain,postoperative pain, iatrogenic pain, complex regional pain syndrome,failed-back pain, soft tissue pain, joint pain, bone pain, central pain,injury pain, arthritic pain, hereditary disease, infectious disease,headache, causalgia, hyperesthesia, sympathetic dystrophy, phantom limbsyndrome, and denervation. This invention is particularly useful in thetreatment of pain of long duration or chronic pain.

A primary object of the invention is provide a method for convenient,long-term management of pain.

One advantage of the invention is that the devices and methods describedherein provide effective management of pain by administration of arelatively small quantity of fentanyl or a fentanyl congener (e.g.,sufentanil), providing adequate pain relief and an improvement inadverse side effects relative to morphine. Given the adverse effects ofopioid analgesics, this advantage is of considerable benefit to thoserequiring pain relief, particularly in relatively long term (e.g., 1-4months) pain situations. Furthermore, the method may be morecost-effective, and thus may make pain management available to a broaderpopulation.

Another advantage of the invention is that the invention can be used todeliver relatively small quantities of fentanyl and fentanyl congenersaccurately and precisely and thus safely delivering such drugs despitethe extreme potency of these drugs compared to morphine. Thus, theinvention allows for the convenient use of these drugs for treatment ofpain ranging in severity from mild to severe.

One particularly surprising advantage of the invention is that an amountof fentanyl or a fentanyl congener sufficient to provide a relativelylong duration of therapy can be stored safely and stably within the bodyand without deleterious effect given the high potency of the subjectcompounds.

Another notable advantage of the invention is that the use of animplantable drug delivery device avoids the need for placement ofexternal needles and/or catheters in the subject, which might providesites susceptible to infection. In addition, use of an implanted deviceincreases patient compliance with a prescribed therapeutic regimen,substantially decreases or completely avoids the risk of abuse of thedrug by the patient or others in contact with the patient, and affordsgreater mobility and easier outpatient management.

Another advantage of the invention is that fentanyl or a fentanylcongener can be delivered into the systemic circulation with suchaccuracy and precision and at such low quantities as to permit long-termuse of such compounds to treat pain.

A further advantage is that a therapeutically effective dose of fentanyland fentanyl congeners can be delivered at such relatively low volumerates, e.g., from about 0.01 μl/day to 2 ml/day so as to minimize tissuedisturbance or trauma.

Another advantage is that fentanyl and fentanyl congeners (e.g.,sufentanil) delivery according to the invention provides for effectivedrug delivery to provide the desired therapeutic effect while avoidinglocal irritation.

Another advantage of the invention is that substantially continuousdelivery of small quantities of fentanyl or fentanyl congener (e.g.,sufentanil) is effective in long-term (e.g., chronic) administration(e.g., from several weeks or from about 1 to 12 months or more).

Another advantage of the invention is that the marked potency of theselected opioids (fentanyl, sufentanil, or other fentanyl congener)relative to other opioids such as morphine allows for its administrationat effective doses in small amounts and volumes that make it aconvenient therapy.

The method of the invention is also advantageous in that since theselected drugs (e.g., sufentanil) are highly lipophilic relative toother opioids, thus facilitating delivery of the drug across theblood-brain barrier. For example, the octanol/water partitioncoefficient of sufentanil is 1,727, compared to a coefficient of 1.4 formorphine. Systemic administration (e.g., by subcutaneous delivery) ofcertain lipophilic fentanyl congeners, e.g., sufentanil, may be aseffective as if the drug were delivered directly to the central nervoussystem.

Yet another advantage is that the invention provides for precisedelivery of the selected fentanyl-comprising or fentanylcongener-comprising formulation, thus allowing delivery of lower dosesand/or for delivery of precisely metered doses at consistent deliveryvolume rates (e.g., on the order of microliters to milliliters perhour).

Still another advantage is that the invention may decrease the severityor incidence of side effects normally associated with use of morphine inpain management.

These and other objects, advantages and features of the presentinvention will become apparent to those persons skilled in the art uponreading the details of the methodology and compositions as more fullyset forth below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates systemic delivery of drug using an implanted drugdelivery device.

FIG. 2 is a perspective view of an exemplary drug delivery device usefulin the present invention.

FIG. 3 illustrates intravenous delivery using a drug delivery deviceimplanted subcutaneously via a catheter positioned for delivery of drugintravenously.

FIG. 4 is a cut-away view of an exemplary drug delivery devicecomprising a catheter.

FIG. 5 is a graph showing release of sufentanil from an exemplaryosmotic pump at a rate of 20 μg/hr.

FIG. 6 is a graph showing cumulative release of sufentanil fromexemplary osmotic pumps at a rate of 20 μg/hr.

FIG. 7 is a graph showing release of sufentanil from exemplary osmoticpumps at a rate of 5 μg/hr.

FIG. 8 is a graph showing the average pumping rates of the pumps ofFIGS. 5 and 7.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before the present device and methods for treatment of pain aredescribed, it is to be understood that this invention is not limited tothe specific methodology, devices, therapeutic formulations, and painsyndromes described as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention which will be limited only by theappended claims.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “adrug delivery device” includes a plurality of such devices and referenceto “the method of delivery” includes reference to equivalent steps andmethods known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this invention belongs. Although any methods, devicesand materials similar or equivalent to those described herein can beused in the practice or testing of the invention, the preferred methods,devices and materials are now described.

All publications mentioned herein are incorporated herein by referencefor the purpose of describing and disclosing the compositions andmethodologies which are described in the publications which might beused in connection with the presently described invention. Thepublications discussed herein are provided solely for their disclosureprior to the filing date of the present application. Nothing herein isto be construed as an admission that the invention is not entitled toantedate such a disclosure by virtue of prior invention.

DEFINITIONS

The term “drug” as used herein is generally meant to refer to fentanylor a fentanyl congener (e.g., sufentanil, alfentanil, lofentanil,carfentanil, remifentanil, trefentanil, and mirfentanil), as well asformulations comprising one or more of these compounds. Use of “drug” orthe phrase “fentanyl or fentanyl congener” is not meant to be limitingto use of, or formulations comprising, only one of these selected opioidcompounds. Furthermore, reference to fentanyl alone or to a selectedfentanyl congener alone, e.g., reference to “sufentanil,” is understoodto be only exemplary of the drugs suitable for delivery according to themethods of the invention, and is not meant to be limiting in any way.

The term “subject” is meant any subject, generally a mammal (e.g.,human, canine, feline, equine, bovine, etc.), in which management ofpain is desired.

The term “systemic delivery” is meant to encompass all parenteral routesof delivery which permit drug to enter into the systemic circulation,e.g., intravenous, intra-arterial, intramuscular, subcutaneous,intra-adipose tissue, intra-lymphatic, etc.

The term “therapeutically effective amount” is meant an amount of atherapeutic agent, or a rate of delivery of a therapeutic agent,effective to facilitate a desired therapeutic effect. The precisedesired therapeutic effect (e.g., the degree of pain relief, and sourceof the pain relieved, etc.) will vary according to the condition to betreated, the formulation to be administered, and a variety of otherfactors that are appreciated by those of ordinary skill in the art. Ingeneral, the method of the invention involves the suppression ormitigation of pain in a subject suffering from pain that may beassociated with any of a variety of identifiable or unidentifiableetiologies.

The term “pain management or treatment” is used here to generallydescribe regression, suppression, or mitigation of pain so as to makethe subject more comfortable as determined by subjective criteria,objective criteria, or both. In general, pain is assessed subjectivelyby patient report, with the health professional taking intoconsideration the patient's age, cultural background, environment, andother psychological background factors known to alter a person'ssubjective reaction to pain.

“Delivery site” as used herein is meant to refer to an area of the bodyto which drug is delivered for entry into the systemic circulation,e.g., a site which allows systemic access of drug delivered to the site.Exemplary delivery sites compatible with systemic delivery of druginclude, but are not necessarily limited to, subcutaneous, intravenous,intra-arterial, intra-muscular, intra-adipose tissue, andintra-lymphatic sites.

The term “implantation site” is used to refer to a site within the bodyof a subject at which a drug delivery device is introduced andpositioned.

“Drug delivery device” as used herein is meant to any implantable devicesuitable for delivering the formulations for pain management accordingto the invention. “Drug delivery device” thus encompasses anyimplantable device with any mechanism of action including diffusive,erodible, or convective systems, e.g., osmotic pumps, biodegradableimplants, electrodiffusion systems, electroosmosis systems, vaporpressure pumps, electrolytic pumps, effervescent pumps, piezoelectricpumps, erosion-based systems, or electromechanical systems.

“Patterned” or “temporal” as used in the context of drug delivery ismeant delivery of drug in a pattern, generally a substantially regularpattern, over a pre-selected period of time (e.g., other than a periodassociated with, for example a bolus injection). “Patterned” or“temporal” drug delivery is meant to encompass delivery of drug at anincreasing, decreasing, substantially constant, or pulsatile, rate orrange of rates (e.g., amount of drug per unit time, or volume of drugformulation for a unit time), and further encompasses delivery that iscontinuous or substantially continuous, or chronic.

The term “controlled drug delivery device” is meant to encompass anydevice wherein the release (e.g., rate, timing of release) of a drug orother desired substance contained therein is controlled by or determinedby the device itself and not the environment of use.

By “substantially continuous” as used in, for example, the context of“substantially continuous subcutaneous infusion” or “substantiallycontinuous delivery” is meant to refer to delivery of drug (e.g.,sufentanil) in a manner that is substantially uninterrupted for apre-selected period of drug delivery (other than a period associatedwith, for example, a bolus injection). Furthermore, “substantiallycontinuous” drug delivery can also encompass delivery of drug at asubstantially constant, pre-selected rate or range of rates (e.g.,amount of drug per unit time, or volume of drug formulation for a unittime) that is substantially uninterrupted for a pre-selected period ofdrug delivery.

Pain Susceptible to Management with the Devices and Methods of theInvention

In general, administration of fentanyl or a fentanyl congener accordingto the invention can be used to facilitate management of pain (e.g.,palliative care through, e.g., systemic or centrally mediated analgesia)that is associated with any of a wide variety of disorders, conditions,or diseases. “Pain” as used herein, unless specifically noted otherwise,is meant to encompass pain of any duration and frequency, including, butnot limited to, acute pain, chronic pain, intermittent pain, and thelike. Causes of pain may be identifiable or unidentifiable. Whereidentifiable, the origin of pain may be, for example, of malignant,non-malignant, infectious, non-infectious, or autoimmune origin. Ofparticular interest is the management of pain associated with disorders,diseases, or conditions that require long-term therapy, e.g., chronicand/or persistent diseases or conditions for which therapy involvestreatment over a period of several days (e.g., about 3 days to 10 days),to several weeks (e.g., about 2 weeks or 4 weeks to 6 weeks), to severalmonths or years, up to including the remaining lifetime of the subject.Subjects who are not presently suffering from a disease or condition,but who are susceptible to such may also benefit from prophylactic painmanagement using the devices and methods of the invention, e.g., priorto traumatic surgery. Pain amenable to therapy according to theinvention may involve prolonged episodes of pain alternating withpain-free intervals, or substantially unremitting pain that varies inseverity.

In general, pain can be nociceptive, somatogenic, neurogenic, orpsychogenic. Somatogenic pain can be muscular or skeletal (i.e.,osteoarthritis, lumbosacral back pain, posttraumatic, myofascial),visceral (i.e., pancreatitis, ulcer, irritable bowel), ischemic (i.e.,arteriosclerosis obliterans), or related to the progression of cancer(e.g., malignant or non-malignant). Neurogenic pain can be due toposttraumatic and postoperative neuralgia, can be related toneuropathies (i.e., diabetes, toxicity, etc.), and can be related tonerve entrapment, facial neuralgia, perineal neuralgia, postamputation,thalamic, causalgia, and reflex sympathetic dystrophy.

Specific examples of conditions, diseases, disorders, and origins ofpain amenable to management according to the present invention include,but are not necessarily limited to, cancer pain (e.g., metastatic ornon-metastatic cancer), inflammatory disease pain, neuropathic pain,postoperative pain, iatrogenic pain (e.g., pain following invasiveprocedures or high dose radiation therapy, e.g., involving scar tissueformation resulting in a debilitating compromise of freedom of motionand substantial pain), complex regional pain syndromes, failed-back pain(e.g., acute or chronic back pain), soft tissue pain, joints and bonepain, central pain, injury (e.g., debilitating injuries, e.g.,paraplegia, quadriplegia, etc., as well as non-debilitating injury(e.g., to back, neck, spine, joints, legs, arms, hands, feet, etc.)),arthritic pain (e.g., rheumatoid arthritis, osteoarthritis, arthriticsymptoms of unknown etiology, etc.), hereditary disease (e.g., sicklecell anemia), infectious disease and resulting syndromes (e.g., Lymedisease, AIDS, etc.), headaches (e.g., migraines), causalgia,hyperesthesia, sympathetic dystrophy, phantom limb syndrome,denervation, and the like. Pain can be associated with any portion(s) ofthe body, e.g., the musculoskeletal system, visceral organs, skin,nervous system, etc.

Cancer pain is an example of one broad category of pain that can bealleviated according to the methods of the invention. One of theunderlying causes of cancer pain is the severe local stretching oftissues by the neoplastic lesion. For example, as the cancer cellsproliferate in an unrestricted manner, the tissues in the local regionof cancer cell proliferation are subjected to mechanical stress requiredto displace tissue and accommodate the increased volume occupied by thetumor mass. When the tumor burden is confined to a small enclosedcompartment, such as the marrow of a bone, the resulting pressure canresult in severe pain. Another cause of cancer pain can result from theaggressive therapies used to combat the patient's cancer, e.g.,radiation therapy, chemotherapy, etc. Such cancer therapies can involvelocalized or widespread tissue damage, resulting in pain.

Pain associated with any type of malignant or non-malignant cancer isamenable to alleviation according to the invention. Specific examples ofcancers that can be associated with pain (due to the nature of thecancer itself or therapy to treat the cancer) include, but are notnecessarily limited to lung cancer, bladder cancer, melanoma, bonecancer, multiple myeloma, brain cancer, non-Hodgkins lymphoma, breastcancer, oral cancers, cervical cancer, ovarian cancer, colon cancer,rectal cancer, pancreatic cancer, dysplastic nevi, endocrine cancer,prostate cancer, head and neck cancers, sarcoma, Hodgkins disease, skincancer, kidney cancer, stomach cancer, leukemia, testicular cancer,liver cancer, uterine cancer, and aplastic anemia. Certain types ofneuropathic pain can also be amenable to treatment according to theinvention.

Back pain, which is also amenable to management using the methods of theinvention, is another broad category of pain that can be alleviated byapplication of the methods of the invention. Back pain is generally dueto one or more of the following six causes: (i) stress on intervertebralfacet joints, caused by slippage, arthritis, wedging, or scoliosis; (ii)radiculopathy, the mechanical compression of the nerve root due tobulging discs or tumors; (iii) tendonitis or tendon sprain; (iv) musclespasm or muscle sprain; (v) ischemia, a local insufficiency incirculatory flow; and (vi) neuropathy, damage to nervous tissue ofmetabolic etiology or arising from cord tumors or central nervous systemdisease.

The methods of the invention can be used to manage pain in patients whoare opioid naive or who are no longer opioid naïve, although due to thepotency of the drugs administered, patients are preferably not opioidnaïve. Exemplary opioid naive patients are those who have not receivedlong-term opioid therapy for pain management. Exemplary non-opioid naivepatients are those who have received short-term or long-term opioidtherapy and have developed tolerance, dependence, or other undesirableside effect. For example, patients who have intractable adverse sideeffects with oral, intravenous, or intrathecal morphine, transdermalfentanyl patches, or conventionally administered subcutaneous infusionsof fentanyl, morphine or other opioid can achieve good analgesia andmaintain favorable side-effects profiles with delivery of fentanyl or afentanyl congener when administered in the dose ranges and/or low volumerates described above.

Fentanyl and Fentanyl Congeners and Formulations

Fentanyl, congeners of fentanyl, and specific derivatives or analogs offentanyl (e.g., other derivatives, particularly 4-anilidopiperidinederivatives of morphine) are contemplated for delivery according to theinvention, although variations within the scope of the invention will bereadily apparent to the ordinarily skilled artisan upon reading thedisclosure provided herein. Exemplary fentanyl congeners include, butare not necessarily limited to sufentanil, alfentanil, lofentanil,carfentanil, remifentanil, trefentanil, and mirfentanil.

The specific fentanyl congener used can vary with a variety of factors,including the type of pain to be alleviated, the patient's toleranceand/or previous exposure to opioids, etc. The relative potency offentanyl or the fentanyl congener may also be considered in selection ofthe drug to be delivered. For example, the rank order of potency offentanyl and selected fentanyl congeners relative to morphine is asfollows: morphine <alfentanil <fentanyl <sufentanil <lofentanil<carfentanil. Fentanyl is estimated to be 292 times, sufentanil, 4,521times, lofentanil 5,440 times, and carfentanil 9,441 times more potentthan morphine. For a review of the pharmacokinetics of sufentanil,fentanyl, and other fentanyl congeners, see, e.g., Meert (1996) Pharm.World Sci. 18:1-15; Scholz et al. 1996 Clin. Pharmacokinet. 31:275-92.

In a preferred embodiment, the drug is the fentanyl congener sufentanil.Sufentanil is preferred because it exhibits an appropriate potency, hasbeen previously administered according to conventional methods, has awide therapeutic index (see Meert (1996) Pharm. World Sci. 18:1-15),exhibits good stability, and provides for reduced side effects whendelivered according to the methods of the invention. Furthermore, theinventors have found that the lipophilicity of sufentanil isparticularly suitable for subcutaneous delivery.

Methods for manufacture of fentanyl, sufentanil and other fentanylcongeners are well known in the art, see, e.g., sufentanil (e.g., U.S.Pat. No. 3,998,834; chemical name:((N-[4-(methyoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylpropanamide2-hydroxy-1,2,3,-propanetricarboxylate (1:1); C₂₂H₃₀N₂O₂S), fentanyl(e.g., U.S. Pat. No. 3,141,823; chemical name:N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide), alfentanil(e.g., U.S. Pat. No. 4,167,574; chemical name:N-[1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide(C₂₁H₃₂N₆O₃)), lofentanil (e.g., U.S. Pat. No. 3,998,834; chemical name:3-methyl-4-[(1-oxopropyl)phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylicacid methyl ester), carfentanil (chemical name:methyl-4-[(1-oxopropyl)phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate(C₂₄H₃₀N₂O₃)), remifentanil (chemical name:3-[4-methoxycarbonyl-4-[(1-oxopropyl)phenylamino]1-piperidine]propanoicacid), trefentanil (chemical name:N-(1-(2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl)-4-phenyl-4-piperidinyl)-N-(2-fluorophenyl)-propanamide,and mirfentanil (chemical name:[N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide).

Fentanyl and fentanyl congeners are discussed in detail in, for example,Goodman and Gilman's The Pharmacological Basis of Therapeutics, Chapter23, “Opioid Analgesics and Antagonists”, pp. 521-555 (9^(th) Ed. 1996);Baly et al. 1991 Med. Res. Rev. 11:403-36 (evolution of the4-anilidopiperidine opioids); and Feldman et al. 1991 J. Med. Chem.34:2202-8 (design, synthesis, and pharmacological evaluation of opioidanalgesics). For additional information on fentanyl and fentanylcongeners, see, e.g., Scholz et al. 1996 Clin. Pharmacokinet. 31:275-92(clinical pharmacokinetics of alfentanil, fentanyl, and sufentanil);Meert 1996 Pharmacy World Sci. 18: 1-15 (describing pharmacotherapy ofmorphine, fentanyl, and fentanyl congeners); Lemmens et al. 1995 Anesth.Analg. 80:1206-11 (pharmacokinetics of mirfentanil); Minto et al., 1997Int. Anesthesiol. Clin. 35:49-65 (review of recently developed opioidanalgesics); James 1994 Expert Opin. Invest. Drugs 3:331-40 (discussionof remifentanil); Rosow 1993 Anesthesiology 79:875-6 (discussion ofremifentanil); Glass 1995 Eur. J. Anaesthesiol. Suppl. 10:73-4.(pharmacology of remifentanil); and Lemmens et al. 1994 Clin. Pharmacol.Ther. 56:261-71 (pharmacokinetics of trefentanil)

Fentanyl or a fentanyl congener can be provided in the formulation asthe opioid base and/or the opioid pharmaceutically acceptable salt. Thepharmaceutically acceptable salt embraces the inorganic and the organicsalt. Representative salts include a member selected from the groupconsisting of hydrobromide, hydrochloride, mucate, citrate, succinate,n-oxide, sulfate, malonate, acetate, phosphate dibasic, phosphatemonobasic, acetate trihydrate, bi(heplafluorobutyrate), maleate,bi(methylcarbamate), bi(pentafluoropropionate), mesylate,bi(pyridine-3-carboxylate), bi(trifluoroacetate), bitartrate,chlorhydrate, fumarate and sulfate pentahydrate.

Fentanyl or a fentanyl congener can be provided in any of a variety offormulations compatible with parenteral delivery, provided that suchformulation is stable (i.e., not subject to degradation to anunacceptable amount at body temperature). The concentration of fentanylor fentanyl congener in the formulation may vary from about 0.1 wt. % toabout 50 or 75 wt. %. The drug can be provided in any form suitable tobe carried by the controlled drug delivery device and releasedparenterally for systemic distribution, e.g., solid, semi-solid, gel,liquid, suspension, emulsion, osmotic dosage formulation, diffusiondosage formulation, erodible formulation, etc. Of particular interest isthe administration of sufentanil in an form suitable for administrationusing an implanted pump, e.g., an osmotic pump.

In one embodiment, the fentanyl or fentanyl congener is present in theformulation in a concentration substantially higher than conventionalformulations, e.g., current commercially available formulations. By“substantially higher,” it is intended that the fentanyl or fentanylcongener is present in the formulation in a concentration of at leastabout 2, at least about 5, at least about 10, at least about 20, atleast about 50, at least about 100, at least about 250, at least about500, at least about 1000, at least about 1500, at least about 2000, atleast about 2500, at least about 3000, at least about 3500, at leastabout 4000, at least about 5000, at least about 6000, at least about7000, at least about 8000, at least about 9000, at least about 10,000times, or greater, than the solubility of fentanyl or fentanyl congenerin aqueous solution.

Formulations of the invention comprise fentanyl or a fentanyl congenerin a concentration of at least about 0.5 mg/mL, 1 mg/mL, 10 mg/mL, 25mg/mL, 50 mg/mL, 75 mg/mL, 100 mg/mL, 150 mg/mL, 200 mg/mL, 225 mg/mL,250 mg/mL, 300 mg/mL, 350 mg/mL, 400 mg/mL, 450 mg/mL, 500 mg/mL, orgreater. Formulations of the invention comprising fentanyl or fentanylcongener are in solution, e.g., are dissolved in a liquid.

Pharmaceutical grade organic or inorganic carriers and/or diluentssuitable for systemic delivery can be included in the formulationssuitable for delivery according to the invention. Such physiologicallyacceptable carriers are well known in the art. Exemplary liquid carriersfor use in accordance with the present invention can be sterilenon-aqueous or aqueous solutions which contain no materials other thanthe active ingredient. In general, hydrophobic solvents are generallypreferred due to the lipophilicity of fentanyl and fentanyl congeners.The formulations can optionally further comprise a buffer such as sodiumphosphate at physiological pH value, physiological saline or both (i.e.,phosphate-buffered saline). Suitable aqueous carriers may optionallyfurther comprise more than one buffer salt, as well as other salts (suchas sodium and potassium chlorides) and/or other solutes.

In some exemplary embodiments, the formulation comprises fentanyl or afentanyl congener (generally as a base) and a low molecular weight(e.g., MW less than about 300 g/mol) alcohol. In these embodiments, thefentanyl or fentanyl congener is present in the formulation in aconcentration of from about 0.5 mg/mL to about 500 mg/mL, from about 1mg/mL to about 450 mg/mL, from about 50 mg/mL to about 400 mg/mL, fromabout 75 mg/mL to about 300 mg/mL, or from about 100 mg/mL to about 250mg/mL. Suitable low molecular weight alcohols include those which arepharmaceutically acceptable, and which preferably comprise an aromaticmoiety, and which are relatively immiscible in water (e.g., less thanabout 5, less than about 4, less than about 3, less than about 2, lessthan about 1 gram can dissolve in 25 ml H₂O), including, but not limitedto, benzyl alcohol, and derivatives thereof. Small amounts of otherpharmaceutically acceptable substances such as other pharmaceuticallyacceptable alcohols, e.g., ethanol, or water, may also be present, and,if present, are present in an amount of less than about 10%, less thanabout 5%, or less than about 1%. In a particular embodiment, theformulation comprises fentanyl or fentanyl congener, with sufentanilbeing of particular interest, in 100% benzyl alcohol.

In additional exemplary embodiments, the formulation comprises fentanylor a fentanyl congener (generally as a base), and a nonionic surfactant,in an alcohol ester, e.g., an ester of a low molecular weight alcohol asdescribed above. In these embodiments, the fentanyl or fentanyl congeneris present in the formulation in a concentration of from about 0.5 mg/mlor 1 mg/mL to about 500 mg/mL, from about 50 mg/mL to about 300 mg/mL,from about 75 mg/mL to about 275 mg/mL, or from about 100 mg/mL to about250 mg/mL. Suitable alcohol esters include those which arepharmaceutically acceptable, which preferably comprise an aromaticmoiety, and which are insoluble in water, including, but not limited to,benzyl benzoate, and derivatives thereof. Small amounts ofpharmaceutically acceptable substances such as pharmaceuticallyacceptable alcohols or other pharmaceutically acceptable alcohol esters,or water, may also be present, and, if present, are present in an amountof less than about 10%, less than about 5%, or less than about 1%. In aparticular embodiment, the alcohol ester is 100% benzyl benzoate, withsufentanil as the fentanyl congener being of particular interest.

Suitable nonionic surfactants include those which are pharmaceuticallyacceptable, including but not limited to, polysorbate, e.g., polysorbate20, polysorbate 40, polysorbate 60; sorbitan trioleate; polyoxyethylenepolyoxypropyleneglycol, e.g., polyoxyethylene(160)glycol, andpolyoxypropylene(30)glycol. Other nonionic surfactants which aresuitable for use in the formulations include nonionic surfactants of thefatty acid polyhydroxy alcohol ester type such as sorbitan monolaurate,monooleate, monostearate or monopalmitate, sorbitan tristearate ortrioleate, adducts of polyoxyethylene and fatty acid polyhydroxy alcoholesters such as polyoxyethylene sorbitan monolaurate, monooleate,monostearate, monopalmitate, tristearate or trioleate, polyethyleneglycol fatty acid esters such as polyoxyethyl stearate, polyethyleneglycol 400 stearate, polyethylene glycol 2000 stearate, in particularethylene oxide-propylene oxide block copolymers of the Pluronics□(Wyandotte) or Synperonic□ (ICI). In particular embodiments, thenonionic surfactant is polysorbate 20, polysorbate 40, polysorbate 60,or sorbitan trioleate, or mixtures of one or more of the foregoing.

In general, a nonionic surfactant is present in the formulation in aconcentration of from about 50 mg/mL to about 200 mg/mL, from about 75mg/mL to about 175 mg/mL, or from about 100 mg/mL to about 150 mg/mL. Ina particular embodiment, the nonionic surfactant is present in theformulation at 100 mg/mL.

Formulations of particular interest for delivery are characterized inthat the fentanyl or fentanyl congener is present in a highconcentration, as described above. The fentanyl or fentanyl congener issoluble in the formulation, i.e., little or no fentanyl or fentanylcongener precipitates are present, and further, little or no fentanyl orfentanyl congener precipitates form when the formulation comes incontact with an aqueous environment such as a body fluid. Precipitatesof fentanyl or fentanyl congeners, when present at all, are present inthe formulation at less than about 10%, less than about 7.5%, less thanabout 5%, less than about 2.5%, less than about 1%, or less than about0.1% by weight of the total fentanyl or fentanyl congener present in theformulation. Whether precipitates have formed can be determined usingany method known in the art, including, but not limited to, visualinspection with the unaided eye, or under low (e.g., 10× or 25×)magnification.

The formulations comprising fentanyl or a fentanyl congener and suitablefor administration according to the invention may comprise additionalactive or inert components that are pharmaceutically acceptable andcompatible with the active ingredient. Suitable excipients can comprisedextrose, glycerol, alcohol (e.g., ethanol), and the like, andcombinations of one or more thereof with vegetable oils, propyleneglycol, polyethylene glycol, benzyl alcohol, benzyl benzoate, dimethylsulfoxide (DMSO), organics, and the like to provide a suitablecomposition. In addition, if desired, the composition can comprisehydrophobic or aqueous surfactants, dispersing agents, wetting oremulsifying agents, isotonic agents, pH buffering agents, dissolutionpromoting agents, stabilizers, antiseptic agents and other typicalauxiliary additives employed in the formulation of pharmaceuticalpreparations.

Exemplary additional active ingredients that can be present in theformulations useful with the invention can include an opioid antagonist(e.g., to further decrease the possibility of addiction or dependence,see, e.g., an exemplary osmotic dosage formulation comprising an opioidagonist and an opioid antagonist is described in U.S. Pat. No.5,866,164.

Implantation and Delivery Sites

The drug delivery device can be implanted at any suitable implantationsite using methods and devices well known in the art. As noted infra, animplantation site is a site within the body of a subject at which a drugdelivery device is introduced and positioned. Implantation sitesinclude, but are not necessarily limited to a subdermal, subcutaneous,intramuscular, or other suitable site within a subject's body.Subcutaneous implantation sites are preferred because of convenience inimplantation and removal of the drug delivery device. In someembodiments, the implantation site is at or near the delivery site(e.g., the delivery site is not distant from the implantation site), andthus should be a site compatible with systemic delivery of drug (e.g., asubcutaneous site). Where the implantation site and the delivery siteare distant, then it is not necessary that the implantation site be asite compatible with systemic delivery of drug. For example, the drugdelivery device can be implanted at a subcutaneous site, and thedelivery site can be an intravenous or other site suitable for systemicdelivery of drug. Delivery of drug from a drug delivery device at animplantation site that is distant from a delivery site can beaccomplished by providing the drug delivery device with a catheter, asdescribed in more detail below.

The delivery site is an area of the body to which drug is delivered forentry into the systemic circulation, i.e., a site which allows systemicaccess of the drug. Delivery sites include, but are not necessarilylimited to, subcutaneous, intravenous, intra-arterial, intra-muscular,intra-adipose tissue, intra-lymphatic and sublingual sites. Subcutaneousdelivery sites are of particular interest in the present application.Exemplary subcutaneous delivery sites include external subcutaneoussites (e.g., under the skin of the arm, shoulder, neck, back, or leg)and internal subcutaneous sites within a body cavity (e.g., within themouth). Delivery to a subcutaneous site further enhances theseadvantages of the invention, since delivery to a subcutaneous siteinvolves the greatest contact with tissue that can readily absorb thedrug. Furthermore, the present invention treats pain by delivery offentanyl or its congeners (e.g., sufentanil), which drugs arelipophilic. The lipophilicity of these drugs further enhances theirabsorption at a delivery site, particularly at a subcutaneous deliverysite.

Delivery of Fentanyl or Fentanyl Congeners

In general, the formulation of fentanyl or fentanyl congener isdelivered at a volume rate that is compatible with the delivery site,and at a dose that is therapeutically effective in reduction of pain(e.g., sufficient to accomplish substantial management of pain) whilereducing the presence or risk of side effects that can be associatedwith administration of opioid drugs.

Subjects suffering from or susceptible to pain can receive alleviationof pain according to the method of the invention for any desired periodof time. In general, administration of fentanyl or fentanyl congeneraccording to the invention can be sustained for several hours (e.g., 2hours, 12 hours, or 24 hours to 48 hours or more), to several days(e.g., 2 to 5 days or more), to several months or years. Typically,delivery can be continued for a period ranging from about 1 month toabout 12 months or more. The fentanyl or fentanyl congener may beadministered to an individual for a period of, for example, from about 2hours to about 72 hours, from about 4 hours to about 36 hours, fromabout 12 hours to about 24 hours, from about 2 days to about 30 days,from about 5 days to about 20 days, from about 7 days or more, fromabout 10 days or more, from about 100 days or more, from about 1 week toabout 4 weeks, from about 1 month to about 24 months, from about 2months to about 12 months, from about 3 months to about 9 months, fromabout 1 month or more, from about 2 months or more, or from about 6months or more; or other ranges of time, including incremental ranges,within these ranges, as needed. This extended period of opioid deliveryis made possible by the ability of the invention to provide bothadequate pain relief, while minimizing the severity of opioid sideeffects (e.g., nausea, vomiting, sedation, confusion, respiratorydepression, etc.). In particular embodiments, the fentanyl or fentanylcongener is delivered to the subject without the need for re-accessingthe device and/or without the need for re-filling the device. In theseembodiments, high-concentration formulations of fentanyl or fentanylcongener are of particular interest.

Preferably, delivery of fentanyl or fentanyl congener is in a patternedfashion, more preferably in a substantially continuous fashion, e.g.,substantially uninterrupted for a pre-selected period of drug delivery,and more preferably at a substantially constant, pre-selected rate orrange of rates (e.g., amount of drug per unit time, or volume of drugformulation for a unit time). The drug is preferably delivered at a lowvolume rate of from about 0.01 μl/day to about 2 ml/day, preferablyabout 0.04 μl/day to about 1 ml/day, generally about 0.2 μl/day to about0.5 ml/day, typically from about 2.0 μl/day to about 0.25 ml/day.

Systemic administration of drug by delivery using an implanted pumpaccording to the invention is particularly preferred where delivery byother routes has become undesirable, e.g., the subject has experiencedintractable adverse side effects with oral, intravenous, or intrathecalmorphine, transdermal fentanyl patches, or conventionally administeredsubcutaneous infusions (e.g., using a syringe driver system or otherdelivery system that requires relatively high volume delivery). Deliveryusing an implanted pump is convenient for the subject, as theimplantation and removal procedures are simple and can be conducted onan out-patient basis where the patient's health allows such.Subcutaneously implanted drug delivery devices also increase patientcompliance, prevent drug diversion and abuse, reduce the risk ofinfection associated with external pumps or other methods that requirerepeated breaking of the skin and/or maintenance of a port foradministration.

Delivery of drug to a subcutaneous site at a low volume rate is aparticularly preferred embodiment of the invention. In general, lowvolume rate drug delivery avoids accumulation of drug at the deliverysite (e.g., depot or pooling effect) by providing for a rate ofadministration that is less than, the same as, or only very slightlygreater than the rate of removal of drug from the delivery site (e.g.,by absorption of drug in tissues at the site, movement of drug away fromthe site by flow of blood or other bodily fluids, etc.). Thus, inaddition to providing an implantable system for delivery of highlypotent drugs such as fentanyl and fentanyl congeners (e.g., sufentanil),the present invention also provides a method for treating pain byelegantly balancing the rates of drug absorption and drug delivery toaccomplish administration of a therapeutically effective amount of drug,while avoiding accumulation of drug at the delivery site.

In one embodiment, a drug delivery device provides for substantiallycontinuous, subcutaneous delivery of drug at a preselected rate. Forexample, for subcutaneous delivery of sufentanil, the drug can bedelivered at a rate of from about 0.01 μg/hr to about 200 μg/hr, usuallyfrom about 0.01 μg/hr, 0.25 μg/hr, or 3 μg/hr to about 85 μg/hr, andtypically between about 5 μg/hr to about 100 μg/hr. In a specificexemplary embodiment, sufentanil is delivered at a rate of from about0.01 μg/hr, 0.1 μg/hr, 0.25 μg/hr, 1 μg/hr, generally up to about 200μg/hr. Appropriate amounts of fentanyl or fentanyl congener can bereadily determined by the ordinarily skilled artisan based upon, forexample, the relative potency of these drugs. The actual dose of drugdelivered will vary with a variety of factors such as the potency andother properties of the selected drug used (e.g., lipophilicity, etc.).

Drug Delivery Devices for Use in the Invention

Any of a variety of controlled drug delivery devices can be used in thepresent invention to accomplish delivery of a drug formulationcomprising fentanyl or fentanyl congener. In general, the drug deliverydevice minimally comprises a controlled drug delivery device and, in oneembodiment, further comprises and a drug delivery catheter, e.g., wherethe implantation site is distant from the delivery site.

Drug delivery devices suitable for use with the present invention cantake advantage of any of a variety of controlled drug release devices.In general, the drug release devices suitable for use in the inventioncomprise a drug reservoir for retaining a drug formulation oralternatively some substrate or matrix which can hold drug (e.g.,polymer, binding solid, etc.). The drug release device can be selectedfrom any of a variety of implantable controlled drug delivery systemknown in the art. Controlled drug release devices suitable for use inthe present invention generally can provide for delivery of the drugfrom the device at a selected or otherwise patterned amount and/or rateto a selected site in the subject.

In some embodiments, the delivery device is one that is adapted fordelivery of fentanyl or fentanyl congener over extended periods of time.Such delivery devices may be adapted for administration of fentanyl orfentanyl congener for several hours (e.g., 2 hours, 12 hours, or 24hours to 48 hours or more), to several days (e.g., 2 to 5 days or more,from about 100 days or more), to several months or years. In some ofthese embodiments, the device is adapted for delivery for a periodranging from about 1 month to about 12 months or more. The drug deliverydevice may be one that is adapted to administer fentanyl or fentanylcongener to an individual for a period of, for example, from about 2hours to about 72 hours, from about 4 hours to about 36 hours, fromabout 12 hours to about 24 hours, from about 2 days to about 30 days,from about 5 days to about 20 days, from about 7 days or more, fromabout 10 days or more, from about 100 days or more; from about 1 week toabout 4 weeks, from about 1 month to about 24 months, from about 2months to about 12 months, from about 3 months to about 9 months, fromabout 1 month or more, from about 2 months or more, or from about 6months or more; or other ranges of time, including incremental ranges,within these ranges, as needed. In these embodiments, high-concentrationformulations of fentanyl or fentanyl congener described herein are ofparticular interest for use in the invention.

Release of drug from the device, particularly controlled release ofdrug, can be accomplished in any of a variety of ways according tomethods well known in the art, e.g., by incorporation of drug into apolymer that provides for substantially controlled diffusion of drugfrom within the polymer, incorporation of drug in a biodegradablepolymer, providing for delivery of drug from an osmotically-drivendevice, etc. Where the drug delivery device comprises a drug deliverycatheter, drug can be delivered through the drug delivery catheter tothe delivery site as a result of capillary action, as a result ofpressure generated from the drug release device, by diffusion, byelectrodiffusion or by electroosmosis through the device and/or thecatheter.

The drug delivery device must be capable of carrying the drugformulation in such quantities and concentration as therapeuticallyrequired, and must provide sufficient protection to the formulation fromattack by body processes for the duration of implantation and delivery.The exterior is thus preferably made of a material that has propertiesto diminish the risk of leakage, cracking, breakage, or distortion so asto prevent expelling of its contents in an uncontrolled manner understresses it would be subjected to during use, e.g., due to physicalforces exerted upon the drug release device as a result of movement bythe subject or physical forces associated with pressure generated withinthe reservoir associated with drug delivery. The drug reservoir or othermeans for holding or containing the drug must also be of such materialas to avoid unintended reactions with the active agent formulation, andis preferably biocompatible (e.g., where the device is implanted, it issubstantially non-reactive with respect to a subject's body or bodyfluids).

Suitable materials for the reservoir or drug holding means for use inthe delivery devices of the invention are well known in the art. Forexample, the reservoir material may comprise a non-reactive polymer or abiocompatible metal or alloy. Suitable polymers include, but are notnecessarily limited to, acrylonitrile polymers such asacrylonitrile-butadiene-styrene polymer, and the like; halogenatedpolymers such as polytetrafluoroethylene, polyurethane,polychlorotrifluoroethylene, copolymer tetrafluoroethylene andhexafluoropropylene; polyethylene vinylacetate (EVA), polyimide;polysulfone; polycarbonate; polyethylene; polypropylene;polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; cellulosicpolymers; and the like. Further exemplary polymers are described in TheHandbook of Common Polymers, Scott and Roff, CRC Press, Cleveland RubberCo., Cleveland, Ohio.

Metallic materials suitable for use in the reservoir of the drug releasedevice include stainless steel, titanium, platinum, tantalum, gold andtheir alloys; gold-plated ferrous alloys; platinum-plated titanium,stainless steel, tantalum, gold and their alloys as well as otherferrous alloys; cobalt-chromium alloys; and titanium nitride-coatedstainless steel, titanium, platinum, tantalum, gold, and their alloys.

Exemplary materials for use in polymeric matrices include, but are notnecessarily limited to, biocompatible polymers, including biostablepolymers and biodegradable polymers. Exemplary biostable polymersinclude, but are not necessarily limited to silicone, polyurethane,polyether urethane, polyether urethane urea, polyamide, polyacetal,polyester, poly ethylene-chlorotrifluoroethylene,polytetrafluoroethylene (PTFE or “Teflon™”), styrene butadiene rubber,polyethylene, polypropylene, polyphenylene oxide-polystyrene,poly-a-chloro-p-xylene, polymethylpentene, polysulfone and other relatedbiostable polymers. Exemplary biodegradable polymers include, but arenot necessarily limited to, polyanhydrides, cyclodestrans,polylactic-glycolic acid, polyorthoesters, n-vinyl alcohol, polyethyleneoxide/polyethylene terephthalate, polyglycolic acid, polylactic acid andother related bioabsorbable polymers.

Where the drug formulation is stored in a reservoir comprising metal ora metal alloy, particularly titanium or a titanium alloy having greaterthan 60%, often greater than 85% titanium is preferred for the mostsize-critical applications, for high payload capability and for longduration applications and for those applications where the formulationis sensitive to body chemistry at the implantation site or where thebody is sensitive to the formulation. Most preferably, the drug deliverydevices are designed for storage with drug at room temperature orhigher.

Drug release devices suitable for use in the invention may be based onany of a variety of modes of operation. For example, the drug releasedevice can be based upon a diffusive system, a convective system, or anerodible system (e.g., an erosion-based system). For example, the drugrelease device can be an osmotic pump, an electroosmotic pump, a vaporpressure pump, or osmotic bursting matrix, e.g., where the drug isincorporated into a polymer and the polymer provides for release of drugformulation concomitant with degradation of a drug-impregnated polymericmaterial (e.g., a biodegradable, drug-impregnated polymeric material).In other embodiments, the drug release device is based upon anelectrodiffusion system, an electrolytic pump, an effervescent pump, apiezoelectric pump, a hydrolytic system, etc.

Drug release devices based upon a mechanical or electromechanicalinfusion pump, can also be suitable for use with the present invention.Examples of such devices include those described in, for example, U.S.Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852, and thelike. In general, the present methods of drug delivery can beaccomplished using any of a variety of refillable, non-exchangeable pumpsystems. Pumps and other convective systems are generally preferred dueto their generally more consistent, controlled release over time.Osmotic pumps are particularly preferred due to their combinedadvantages of more consistent controlled release and relatively smallsize. Of the osmotic pumps, the DUROS™ osmotic pump is particularlypreferred (see, e.g., WO 97/27840 and U.S. Pat. Nos. 5,985,305 and5,728,396)).

In one embodiment, the drug release device is a controlled drug releasedevice in the form of an osmotically-driven device. Preferredosmotically-driven drug release systems are those that can provide forrelease of drug in a range of rates of from about 0.01 μg/hr to about200 μg/hr, and which can be delivered at a volume rate of from about0.01 μl/day to about 100 μl/day (i.e., from about 0.0004 μl/hr to about4 μl/hr), preferably from about 0.04 μl/day to about 10 μl/day,generally from about 0.2 μl/day to about 5 μl/day, typically from about0.5 μl/day to about 1 μl/day. In one embodiment, the volume/timedelivery rate is substantially constant (e.g., delivery is generally ata rate ± about 5% to 10% of the cited volume over the cited time period,e.g., a volume rate of about

In general, the drug delivery devices suitable for use in the inventionare those that can deliver drug at a low dose, e.g., for sufentanil fromabout 0.01 μg/hr to about 200 μg/hr, and preferably at a low volume ratee.g., on the order of nanoliters to microliters per day. In oneembodiment, a volume rate of from about 0.01 μl/day to about 2 ml/day isaccomplished by delivery of about 80 μl/hour over a period of 24 hours,with the delivery rate over that 24 hours period fluctuating over thatperiod by about ±5% to 10%. Exemplary osmotically-driven devicessuitable for use in the invention include, but are not necessarilylimited to, those described in U.S. Pat. Nos. 3,760,984; 3,845,770;3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880;4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139;4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614;5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like.

Delivery of Fentanyl or Fentanyl Congener Using a Drug Delivery DeviceComprising a Drug Delivery Catheter

In some embodiments it may be desirable to provide a drug deliverycatheter with the drug delivery device, e.g., where the implantationsite and the desired delivery site are not the same or adjacent. Thedrug delivery catheter is generally a substantially hollow elongatemember having a first end (or “proximal” end) associated with the drugrelease device of the drug delivery device, and a second end (or“distal” end) for delivery of the drug-comprising formulation to adesired delivery site. Where a drug delivery catheter is used, a firstend of the drug delivery catheter is associated with or attached to thedrug delivery device so that the lumen of the drug delivery catheter isin communication with the drug reservoir in the drug delivery device, sothat a formulation contained in a drug reservoir can move into the drugdelivery catheter, and out a delivery outlet of the catheter which ispositioned at the desired delivery site.

The body of the catheter defines a lumen, which lumen is to have adiameter compatible with providing leak-proof delivery of drugformulation from the drug delivery device. Where the drug deliverydevice dispenses drug by convection (as in, e.g., osmotic drug deliverysystems), the size of the catheter lumen leading from the reservoir ofthe drug release system can be designed as described by Theeuwes (1975)J. Pharm. Sci. 64:1987-91.

The body of the catheter can be of any of a variety of dimensions andgeometries (e.g., curved, substantially straight, tapered, etc.), thatcan be selected according to their suitability for the intended site fordrug delivery. The distal end of the drug delivery catheter can providea distinct opening for delivery of drug, or as a series of openings.

The drug delivery catheter may be produced from any of a variety ofsuitable materials, and may be manufactured from the same or differentmaterial as the reservoir of the drug release device. Impermeablematerials suitable for use in production of the controlled drug releasedevice as described above are generally suitable for use in theproduction of the drug delivery catheter. Exemplary materials from whichthe drug delivery catheter can be manufactured include, but are notnecessarily limited to, polymers; metals; glasses; polyolefins (highdensity polyethylene (HDPE), low density polyethylene (LDPE), linear lowdensity polyethylene (LLDPE), polypropylene (PP), and the like); nylons;polyethylene terephtholate; silicones; urethanes; liquid crystalpolymers; PEBAX®; HYTREL®; TEFLON®; perfluoroethylene (PFE)perfluoroalkoxy resins (PFA); poly(methyl methacrylate) (PMMA);multilaminates of polymer, metals, and/or glass; nitinol; and the like.

The drug delivery catheter can comprise additional materials or agents(e.g., coatings on the external or internal catheter body surface(s)) tofacilitate placement of the drug delivery catheter and/or to provideother desirable characteristics to the catheter. For example, the drugdelivery catheter inner and/or outer walls can be coated with silver orotherwise coated or treated with antimicrobial agents, thus furtherreducing the risk of infection at the site of implantation and drugdelivery.

In one embodiment, the drug delivery catheter is primed with adrug-comprising formulation, e.g., is substantially pre-filled with drugprior to implantation. Priming of the drug delivery catheter reducesdelivery start-up time, i.e., time related to movement of the drug fromthe drug delivery device to the distal end of the drug deliverycatheter. This feature is particularly advantageous in the presentinvention where the drug release device of the drug delivery devicereleases sufentanil at relatively low flow rates.

FIG. 1 illustrates one embodiment of the invention, wherein fentanyl ora fentanyl congener is delivered from an implanted drug delivery devicethat provides for sustained, controlled release of fentanyl or fentanylcongener from a drug reservoir to a subcutaneous site. In this example,the drug delivery device 10 is implanted at a subcutaneous site in thepatient's arm 5. Flow of drug from the device's drug reservoir and tothe subcutaneous site is illustrated by arrows 200. FIG. 2 provides aperspective view of the exemplary drug delivery device 10 implanted inFIG. 1. The drug delivery device 10 comprises proximal and distal ends11 and 12, with the distal end defining an orifice 15 through which drugexits the drug reservoir 30 for delivery to the subcutaneous site. Inthe exemplary device 10, controlled release of drug from the reservoir30 is provided by an osmotic engine comprising a piston 41 and anchamber comprising an osmotic engine 42.

FIG. 3 illustrates an alternative embodiment in which the drug deliverysystem 100 comprises a drug delivery device 10 and a drug deliverycatheter 20. In the example in FIG. 3, the drug release device portionis maintained at a subcutaneous implantation site and the distal end ofthe drug delivery catheter 20 is implanted at an intravenous deliverysite. As shown in the cut-away of the drug delivery device in FIG. 4,the drug delivery system 100 comprises a drug delivery device 10 and adrug delivery catheter 20. The walls of the drug delivery catheterdefine a lumen, and the drug delivery catheter is associated with thedrug delivery device 10 so that a drug delivery pathway is provided fromthe drug reservoir 30, through orifice 15, and out the distal end 12 ofthe drug delivery device. The catheter 20 can be positioned for systemicdelivery of drug to, for example, vein 7.

Methods for implanting or otherwise positioning drug delivery devicesfor subcutaneous delivery of a drug are well known in the art. Ingeneral, placement of the drug delivery device will be accomplishedusing methods and tools that are well known in the art, and performedunder aseptic conditions with at least some local or general anesthesiaadministered to the subject. In one embodiment, the drug delivery deviceis implanted using an implanter such as the device provided in, forexample, U.S. Design Pat. No. D402,757; or New Zealand Certificate ofRegistration of Design No. 29353. Removal and/or replacement of drugdelivery devices can also be accomplished using tools and methods thatare readily available.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for.

Example 1 Treatment Regimen for Subcutaneous Delivery of Fentanyl orFentanyl Congener Via DUROS™ Pump

1. Evaluation of Patient.

The physician first examines the potential patient and evaluates thepatient's history to determine if the patient has pain that amenable totreatment by opioids and can safely tolerate such treatment.

2. Selection of Appropriate Dose.

If the physician decides to proceed with treatment in accordance withthis invention, the physician determines the appropriate dose of drug(e.g., sufentanil) to be administered to the patient. This determinationcan be performed in a variety of ways. If the patient is already usingcertain medication to control pain (e.g., oral morphine or the fentanyltransdermal patch), the physician can attempt to correlate the dose ofmedication previously used by the patient to an appropriate dose of theselected drug (e.g., fentanyl or fentanyl congener such as sufentanil)when infused subcutaneously. This correlation can be made by referenceto dose conversion information (e.g., a dose conversion chart) betweenthe previous medication and the selected drug, if such dose conversioninformation exists. If dose conversion information does not exist forthe previous medications and the selected drug, the physician can firstswitch the patient from the previous medications to another medicationfor which there exists dose conversion information with the selecteddrug (e.g., fentanyl or fentanyl congener, e.g., sufentanil).

In the alternative to resorting to dose conversion information, or ifsuch information does not exist, the physician can determine theappropriate dose of drug to treat such patient by infusing the selecteddrug (e.g., fentanyl or fentanyl congener, e.g., sufentanil)subcutaneously by means of an external pump and adjusting such infusionrates until the proper dose to control the pain with minimal sideeffects is located.

3. Implantation of DUROS™ Pump.

Once the physician has determined the appropriate dose of fentanyl orfentanyl congener (e.g., sufentanil), then the physician selects aDUROS™ Pump containing a formulation comprising the selected drug (e.g.,sufentanil) that is capable of delivering the required dosage for up to3 months. The physician will then implant the DUROS™ Pump into thesubcutaneous tissue at the inside of the upper arm of the patient.

4. Treatment of Pain.

Once the DUROS™ Pump has become activated by implantation, theformulation of fentanyl or fentanyl congener (e.g., sufentanil) will bedelivered systemically to control pain for up to 3 months. Treatment canbe stopped prior to the end of such 3 months by explanting the DUROS™Pump. If treatment is desired beyond 3 months, the expended DUROS™ Pumpcan be explanted and a replacement DUROS™ Pump may be implanted in thesame subcutaneous location.

Example 2 DUROS™ Pump Useful for Delivery of Sufentanil

The following is a description of exemplary drug loading parameters of aDUROS™ osmotic pump used for the delivery of sufentanil. The parametersare based on a nominal fill volume of the pump of 155 μl, with a nominalvolumetric delivery rate of 1.4 μl/day for a nominal duration of 110days (to ensure that a target delivery period of 90 days is achieved).An exemplary DUROS™ pump useful in this protocol is illustrated in FIG.2, and is approximately 3.76 mm in diameter and 44.21 mm in length.

TABLE 1 Loading Parameters mg Dose Dose delivered Nominal NominalDUROS ™ wt/vol % rate rate μg delivered over 110 Rate Rate Residenceformulation μg/hr μg/day over 110 days days μl/day μl/hr Volume load 2.560 6600 6.6 1.4 0.058 155 4.28 5 120 10800 10.8 1.4 0.058 155 8.57 7.5180 16200 16.2 1.4 0.058 155 12.6 10 240 21600 21.6 1.4 0.058 155 17.120 460 43200 43.2 1.4 0.058 155 34.3These parameters thus dictate the amount of drug to be included in theformulation of the pump in order to provide for delivery at the selecteddose rate for an approximately 110 day period (e.g., about 3 months).

Example 3 Formulations Comprising Sufentanil in Benzyl Alcohol

397 mg/mL Formulation

3.97 g of sufentanil base were weighed out and added to a portion ofbenzyl alcohol. The drug was dissolved in the benzyl alcohol by stirringwith a magnetic stirrer. When the resultant preparation was clear,additional benzyl alcohol was added to obtain 10 mL of formulation. Theresultant formulation concentration was 397 mg/mL.

310 mg/mL Formulation

3.1 g of sufentanil base were weighed out and added to a portion ofbenzyl alcohol. The drug was dissolved in the benzyl alcohol by stirringwith a magnetic stirrer. When the resultant preparation was clear,additional benzyl alcohol was added to obtain 10 mL of formulation. Theresultant formulation concentration was 310 mg/mL.

Example 4 Formulations Comprising Sufentanil in Benzyl Benzoate

248 mg/mL Formulation

The vehicle solution was prepared by adding 3 mL of polysorbate 20 tosufficient benzyl benzoate to make 30 mL of solution. The mixture wasstirred using a magnetic stirrer until the polysorbate 20 was dispersedin the benzyl benzoate. 7.44 g sufentanil base was weighed out and addedto a portion of the vehicle solution. The drug was dissolved bysonicating the flask in a sonication bath. When the resultantpreparation was clear, an additional quantity of the vehicle was addedto obtain 30 mL of formulation. The resultant formulation concentrationwas 248 mg/mL.

77 mg/mL Formulation

The vehicle solution was prepared by adding 3 mL of polysorbate 20 tosufficient benzyl benzoate to make 30 mL of solution. The mixture wasstirred using a magnetic stirrer until the polysorbate 20 was dispersedin the benzyl benzoate. 2.322 g sufentanil base was weighed out andadded to a portion of the vehicle solution. The drug was dissolved bysonicating the flask in a sonication bath. When the resultantpreparation was clear, an additional quantity of the vehicle was addedto obtain 30 mL of formulation. The resultant formulation concentrationwas 77.4 mg/mL.

Example 5 Release of Sufentanil from DUROS™ Osmotic Pump

The release of drug from a DUROS™ osmotic pump at 37° C. was tested invitro at either 20 μg/hr or 5 μg/hr drug dose rates. Five differentsystems (five different pumps) were tested for each of the drug deliveryrates (20 μg/hr and 5 μg/hr) over a 48 day period.

The release media (RM) is prepared from a phosphate buffered saline(PBS) solution, available commercially as a powder preparation andprepared according to manufacturer's directions. 5% polysorbate 20 wasadded to the media prior to bringing it to final volume. This solutionis the release media (RM). 6 mL of RM was dispensed into a 15 mL conicalpolypropylene tube, with one tube prepared for each system to be tested.The tubes were placed in a 37° C. water bath and allowed to reachtemperature.

A system containing sufentanil is placed into each tube with orifice enddown, and completely immersed in the RM. At desired time intervals, thesystem is removed from the tube using a transfer rod. The system isplaced (orifice end down) into a new tube of RM which has beenequilibrated in the water bath. An example of time intervals is 0.5hours, 1, 2, 3, 4, 5, 6, 7, 14, 28, 35 days, continuing weekly untildelivery is complete.

In order to determine the amount of sufentanil released, 4 mL ofacetonitrile was added to each sample test tube and mixed thoroughly.The sample is then assayed to determine the amount of sufentanilreleased during the time interval. Sufentanil in the samples wasquantitated by HPLC or other methodology capable of quantitatingsufentanil in the presence of formulation and RM. The amount releasedper unit time was calculated for each interval, and a release rateprofile prepared by plotting the amount released per unit time on they-axis against the mean time interval on the x-axis.

The results for the 20 μg/hr system are provided in FIG. 5, with thecumulative release provided in FIG. 6. The results for the 5 μg/hrsystem are provided in FIG. 7. The average pumping rate for each group(the 20 μg/hr group of pumps and the 5 μg/hr group of pumps) is providedin FIG. 8. The results demonstrate that controlled, continuous, andprecise low volume release of the potent opioid sufentanil is achievedwith a DUROS™ osmotic implanted pump. In vitro release by the pump iscorrelated to in vivo release because the volume dispensed form the pumpis a pure function of the pump and is independent of the environmentsurrounding the pump. Thus, these same pumps are expected to perform thesame in vivo as in vitro.

1.-47. (canceled)
 48. A method for treating pain in a subject, themethod comprising systemic administration of sufentanil to the subjectat a therapeutically effective rate to provide substantially continuousdelivery of sufentanil at about 10 μg/hr over a period of at least 24hours, wherein said administering induces systemic analgesia in thesubject.
 49. The method of claim 48, wherein said period is at least 3days.
 50. The method of claim 48, wherein said period is at least 5days.
 51. The method of claim 48, wherein said period is at least 10days.
 52. The method of claim 48, wherein said period is at least 30days.
 53. The method of claim 48, wherein said period is at least 90days.
 54. The method of claim 48, wherein said period is at least 1month.